chr11-128911903-G-A

Position:

chr11-128911903-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4BP6_Very_StrongBS2

The NM_000890.5(KCNJ5):c.630G>A(p.Met210Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,607,316 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

KCNJ5
NM_000890.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.65

Variant links:

Genes affected

KCNJ5 (HGNC:6266): (potassium inwardly rectifying channel subfamily J member 5) This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas. [provided by RefSeq, Aug 2017]

KCNJ5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 233) in uniprot entity KCNJ5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000890.5

BP4

Computational evidence support a benign effect (MetaRNN=0.30572316).

BP6

Variant 11-128911903-G-A is Benign according to our data. Variant chr11-128911903-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 404092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ5	NM_000890.5 linkuse as main transcript	c.630G>A	p.Met210Ile	missense_variant	2/3	ENST00000529694.6	NP_000881.3	P48544A0A5J6E2W8
KCNJ5	NM_001354169.2 linkuse as main transcript	c.630G>A	p.Met210Ile	missense_variant	3/4		NP_001341098.1
KCNJ5	XM_011542810.4 linkuse as main transcript	c.630G>A	p.Met210Ile	missense_variant	2/3		XP_011541112.1	P48544A0A5J6E2W8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNJ5	ENST00000529694.6 linkuse as main transcript	c.630G>A	p.Met210Ile	missense_variant	2/3	1	NM_000890.5	ENSP00000433295.1	P48544
KCNJ5	ENST00000338350.4 linkuse as main transcript	c.630G>A	p.Met210Ile	missense_variant	3/4	1		ENSP00000339960.4	P48544
KCNJ5	ENST00000533599.1 linkuse as main transcript	c.630G>A	p.Met210Ile	missense_variant	1/2	1		ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000220

AC:

AN:

249646

Hom.:

AF XY:

0.000289

AC XY:

AN XY:

134816

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000327

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000228

AC:

332

AN:

1455140

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

175

AN XY:

722474

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000360

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000271

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.000151

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000258

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KCNJ5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2019

This variant is associated with the following publications: (PMID: 21311022) -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.75

D;D;D

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.028

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

.;.;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.9

L;L;L

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.26

Sift

Benign

0.049

D;D;D

Sift4G

Benign

0.33

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.14

MutPred

0.34

Gain of catalytic residue at L215 (P = 0.1041);Gain of catalytic residue at L215 (P = 0.1041);Gain of catalytic residue at L215 (P = 0.1041);

MVP

0.89

MPC

0.45

ClinPred

0.085

GERP RS

3.5

Varity_R

0.26

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over